Work

Chromatin-site-specific accessibility: A microtopography-regulated door into the stem cell fate

Year: 2024

Type: article

Abstract: Biomaterials engineered to mimic extracellular matrix (ECM) topography play a pivotal role in tissue engineering. Previous research indicates that certain biomimetic topography can guide stem cells towards multiple specific lineages. However, the mechanisms by which these topographic cues prime multilineage differentiation remain largely elusive. In this study, we show that microtopography influences nuclear tension in MSCs through a mechanotransductive feedback mechanism, which in turn shapes chromatin site-specific accessibility patterns and finally determines the stem cell lineage commitment. When cultured on an aligned substrate, MSCs show high cytoskeletal tension along the fiber direction, resulting in anisotropic nucleus tensile stress. This further leads to the opening of chromatin sites possessing neurogenic, myogenic, and tenogenic genes through the regulation of transcription factors such as TLX. On the other hand, when MSCs are laid on a random substrate, they experience isotropic nucleus stress, leading to the opening of chromatin sites possessing osteogenic and chondrogenic genes through the regulation of RUNX family transcription factors. Collectively, our results show that aligned and random microtopography induce site-specific chromatin stretch and lineage-specific gene expression in MSCs, leading to their priming for specific lineages. Our study thus proposes a novel concept for topographic cues influencing cell behavior and fate during tissue repair and regeneration.

Source: Cell Reports

DOI: 10.1016/j.celrep.2024.115106